Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring

Definitions

• the invention belongs to the field of natural medicine and medicinal chemistry, and relates to a novel saponin I derivative, in particular to a 5,-position acylated furanoarabinyl saponin I derivative, and a method for preparing the same, comprising the compound Composition and its use in the preparation of anti-tumor drugs.
• Background technique
• Polyphyllin l also known as Polyphyllin D; abbreviated as PPD or PP I
• PPD Polyphyllin D
• PP I Polyphyllin D
• 4-0-furan arabinosyl-2-0-pyranpyrose- ⁇ -D-glucopyranosyl Diosgenin is a small molecular monomer extracted from the Chinese herbal medicine (Paris Polyphylla), also known as the seven-leaf flower.
• the heavy building has antibacterial and anti-inflammatory effects, analgesic stabilization and anti-tumor effect. It is found that the main active ingredient, saponin I, exerts anti-tumor effect mainly in the way of inducing apoptosis, and has obvious inhibitory effects on various tumor cells.
• Xiao Meifang et al. investigated the effect of saponin I on proliferation and apoptosis of human hepatocellular carcinoma cell line SMMC-7721 in vitro. And related mechanisms. Studies have shown that saponin I can inhibit the proliferation of liver cancer SMMC-7721 cells in a time- and concentration-dependent manner. It may be that saponin I inhibits the growth of hepatoma cells by blocking the growth of tumor cells and inducing apoptosis. . (Xiao Meifang et al, the effect of heavy saponin I on proliferation and apoptosis of hepatoma cells. Life science research.
• the invention modifies the 5'-furan arabinose group of the saponin I of the saponin I, and the antitumor activity of the compound obtained is doubled compared with the saponin I, which is So far, all the domestic and foreign literatures have not been reported, so these compounds are expected to be developed into clinical anti-tumor drugs. Summary of the invention
• One of the objects of the present invention is to provide a novel 5,-position acylated furan arabinose heavy saponin I derivative of the formula (I) or a pharmaceutically acceptable adduct, complex or salt thereof:
• R 2 is selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted C 2 -C 6 anhydrocarbyl, substituted or unsubstituted c 3 -c 7 cycloalkyl, substituted or unsubstituted C 3 -c 7 cycloalkylene, substituted or unsubstituted aryl C r C 6 alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted heteroaryl, substituted or unsubstituted C r C 6 alkanoyl or substituted or unsubstituted aroyl;
• R 2 is selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted C 2 -C 7 anhydrocarbyl, substituted or unsubstituted C 3 a C 7 cycloalkyl group, a substituted or unsubstit
• a second object of the present invention is to provide a process for the preparation of the 5,-position acylated furanoarabinyl heavy saponin I derivative of the general formula (I) of the present invention:
• the 5'-position acylated furanoarabinyl saponin I derivative (I; is hydrogen) can be isolated from the natural extract of the heavy saponin I and the corresponding organic acid R 2 C0 2 H in the presence of a condensing agent or catalyst Condensed and esterified; it can also be composed of saponin I and the corresponding organic acid chloride
• R 2 COCl or an organic acid anhydride (R 2 CO) 20 is condensed and esterified in the presence of a condensing agent or an alkaline agent; or an organic acid R 2 C0 2 H is activated to form an intermediate, and then with saponin I
• the reaction produces a 5'-position acylated furan arabinosyl heavy saponin I derivative (I; is hydrogen); the hydroxy group of the furan arabinose group of the saponin I can also be activated to form an intermediate, and then with the organic acid R 2 C0 2 H reaction to form a 5'-position acylated furanoarabinyl heavy saponin I derivative (I;
• a third object of the present invention is to provide a pharmaceutical composition comprising a compound of the present invention, the pharmaceutical composition comprising at least one compound of the present invention, and optionally a pharmaceutically acceptable excipient.
• a fourth object of the present invention is to provide a use of a compound of the present invention or a pharmaceutical composition comprising the same for the preparation of a medicament, particularly an antitumor medicament. Accordingly, the invention provides a method of treating a tumor patient comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the invention.
• the tumor is particularly selected from the group consisting of leukemia, multiple myeloma, Lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, human cervical cancer, glioma, nasopharyngeal carcinoma, laryngeal cancer, esophageal cancer, middle ear tumor , prostate cancer, etc.
• the invention also relates to compounds of the invention for use in the treatment of tumors. detailed description
• the present invention relates to a novel 5,-position acylated furanoarabinyl saponin I derivative of the formula (I) or a pharmaceutically acceptable adduct, complex or salt thereof.
• R 2 is selected from H, substituted or unsubstituted C r C 6 alkyl, substituted or unsubstituted C 2 -C 7 fluorene, substituted or unsubstituted C 3 - a C 7 cycloalkyl group, a substituted or unsubstituted C 3 -C
• the invention relates to compounds of formula I, wherein preference is given to H.
• R 2 is preferably a substituted or unsubstituted aryl group which is a phenyl group.
• R 2 CO is selected from the relative An organic acid, an organic acid chloride, or an organic acid anhydride.
• the invention relates to compounds of formula I, wherein preference is given to H.
• R 2 is preferably a substituted or unsubstituted heteroaryl group which is a five- or six-membered aromatic ring group containing a nitrogen, oxygen or sulfur hetero atom; the heteroaryl group in R 2 is more preferably a furyl group , thienyl, pyridyl or pyrrolyl.
• R 2 CO is selected from the corresponding organic acids, organic acid chlorides, or organic acid anhydrides.
• R 2 is preferably a substituted or unsubstituted dC 6 alkyl group, a substituted or unsubstituted C 2 -C 7 fluorene hydrocarbon group, a substituted or unsubstituted C 3 -C 7 cycloalkyl group or a substituted or unsubstituted C 3 -C 7 cyclic anthracenyl; more preferably R 2 is cyclopropyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclohexyl, methyl, ethyl, propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, aminobutyl, arylmethyl, or arylethyl.
• R 2 CO is selected from the corresponding organic acids, organic acid chlorides, or organic acid anhydrides.
• the invention relates to compounds of formula I wherein R 2 is selected from the group consisting of halogen, amino, -NH 2-n (CC 6 1 ⁇ 2) n , - NH 2-n (C 3 -C) 6 cycloalkyl) a n, nitro, cyano, hydroxy, trifluoromethyl, dC 6 alkoxy, mercapto or alkylthio dC 6 or more substituents, where n is an integer of 1 or 2, More preferably, the substituent is fluorine, chlorine, bromine, nitro, amino, cyano, methoxy, ethoxy, propoxy, methyl, ethyl, propyl, isopropyl, trifluoromethyl , trifluoromethoxy, n-butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, cyclopropyla
• the present invention relates to compounds of the general formula (I) of the present invention in the form of their salts, solvates, hydrates, adducts, complexes, polymorphs or prodrugs.
• C r C 6 alkyl refers to straight or branched chain containing 1 to 6 carbon atoms, a substituted or non-substituted alkane.
• Examples of C r C 6 alkane groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, t-butyl, n-pentyl, n-hexyl, and n-icosyl.
• C 2 -C 6 ⁇ alkyl refers to a straight or branched chain, substituted or 2-6 carbon atoms. Unsubstituted anthracene hydrocarbon group.
• Examples of the c 2 -c 6 fluorene hydrocarbon group include, but are not limited to, an ethyl fluorenyl group, a fluorenyl group, and a stilbene hydrocarbon group.
• C 4 -C 8 conjugated hydrocarbon group means a straight or branched, substituted or unsubstituted conjugated hydrocarbon group having 4 to 8 carbon atoms. C 4 -C 2 .
• conjugated hydrocarbyl groups include, but are not limited to, conjugated dihydrocarbyl groups.
• C 3 -C 7 cycloalkyl or "C 3 -C 7 cycloalkyl hydrocarbyl” refers to a hydrocarbyl group of a 3-7 membered monocyclic ring system having a saturated or unsaturated ring, a C 3 -C 7 cycloalkyl group or
• the cycloaliphatic group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclopropenyl group, and a cyclohexyl group.
• aryl C r C 6 alkyl refers to a heteroatom-free aryl C r C 6 alkyl group.
• aryl refers to a monocarbocyclic aryl group or a fused or non-fused polycarbocyclic aryl group containing 6 to 14 (eg, 6 to 12, 6 to 20) carbon atoms, in a multicarbocyclic ring. In the case, as long as one carbon ring is aromatic.
• the aryl group also includes an aryl group fused to a heterocyclic group. Examples of the aryl group are a phenyl group, a biphenyl group, a naphthyl group, a 5,6,7,8-tetrahydronaphthyl group, a 2.3-dihydrobenzofuranyl group and the like.
• heteroaryl refers to an aromatic ring group containing from 1 to 4 heteroatoms (e.g. 1, 2, 3 or 4 heteroatoms) as a ring member. Heteroatoms refer to nitrogen, oxygen or sulfur.
• the heteroaryl group may be a monocyclic heteroaryl group having 5 to 7 ring atoms or a bicyclic heteroaryl group having 7 to 11 ring atoms. As long as one ring of the bicyclic aryl group is an aromatic heterocyclic ring, the other may be aromatic or non-aromatic, hetero atom-containing or hetero atom-free.
• heteroaryl group examples include, for example, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolyl group, pyridyl group, pyrimidinyl group, furyl group, thienyl group, isoxazolyl group, fluorenyl group and the like.
• heterocyclyl refers to a non-aromatic cyclic group containing from 1 to 4 heteroatoms (e.g., 1, 2, 3 or 4 heteroatoms) as ring members. Heteroatoms refer to nitrogen, oxygen or sulfur.
• the heterocyclic group may be a monocyclic heterocyclic group having 4 to 8 ring atoms (for example, a 4-7 membered ring, a 5-7 membered ring, a 5-6 membered ring), or a double ring having 7 to 1 ring atoms. Heterocyclic group.
• the heterocyclic group may be aromatic or non-aromatic.
• heterocyclic groups are azetidinyl, pyrrolidinyl, pyrrolinyl, tetrahydrofuranyl, dihydrofuranyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyran Base, tetrahydrothiol and the like.
• amino acid refers to both natural and unnatural amino acids.
• halogen means fluoro, chloro, bromo or iodo.
• dc 6 alkoxy refers to -O-cc 6 alkyl and -oc 3 -c 6 cycloalkyl.
• dc 6 alkylthio refers to -S-cc 6 alkyl and -sc 3 -c 6 cycloalkyl.
• pharmaceutically acceptable admixtures and complexes of the compounds of formula (I) refers to products in which the compounds of the present invention are further combined with other small molecules or biomacromolecules by non-chemical or non-covalent intramolecular forces.
• the term "pharmaceutically acceptable salts of the compounds of formula (I)” refers to organic acid salts of the compounds of the invention with pharmaceutically acceptable anionic organic acids, including but not Restricted to tosylate, mesylate, malate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, lactate, alpha-ketone Glutarates and alpha-glycerol phosphates; suitable inorganic salts may also be formed, including but not limited to hydrochlorides, sulfates, nitrates, bicarbonates and carbonates, phosphates, hydrobromides, hydrogens Iodate and the like.
• compositions can be obtained using standard procedures well known in the art, for example, by the addition of a sufficient amount of a basic compound and a suitable pharmaceutically acceptable anion.
• polymorph refers to the solid crystalline form of a compound of the invention or a complex thereof. Different polymorphs of the same compound may exhibit different physical, chemical and/or spectral properties. Different physical properties include, but are not limited to, stability (eg, for heat or light), compressibility and density (important for formulation and product production), and dissolution rate (which can affect bioabsorbability and availability).
• Differences in stability can result in chemical reactivity (eg, differential oxidation, such that when formulated from one polymorph, fades faster than when formed from another polymorph) or mechanical properties (eg, as storage) Changes in the kinetically favorable polymorphic tablet granules converted to thermodynamically more stable polymorphs) or both (for example, a polymorphic tablet is more susceptible to breakage at high humidity) .
• the different physical properties of polymorphs can affect their processing. For example, one polymorph may be more likely to form a solvate than the other or may be more difficult to filter or wash away than the other due to, for example, the shape or size distribution of its particles.
• hydrate refers to a compound of the present invention or a salt thereof, which One step comprises stoichiometric or non-stoichiometric water bound by non-covalent intermolecular forces.
• prodrug refers to a derivative that can be hydrolyzed, oxidized, or otherwise reacted under biological conditions (in vitro or in vivo) to provide a compound of the invention. Prodrugs undergo this reaction to become active compounds only under biological conditions, or they are active in their unreacted form. Prodrugs can generally be prepared using well-known methods, for example, 1 Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E.
• the 25 chiral centers of the 5'-acylated acyl arabinosyl saponin I derivative of the present invention have a stereochemical structure represented by the structural formula of Formula I.
• the definitions and conventions for stereochemistry used herein generally follow MCGRAW-HILL DICTIONARY OF CHEMICAL TERMS (SP Parker, Ed., McGraw-Hill Book Company, New York, 1984); ELIEL, E. and WILEN, S., STEREOCHEMISTRY OF ORGANIC COMPOUNDS (John Wiley & Sons, Inc., New York, 1994).
• Many organic compounds exist in optically active forms, i.e., they have the ability to rotate planes that are plane polarized.
• treating generally refers to obtaining the desired pharmacological and/or physiological effects. This effect, in whole or in part, prevents the disease or its symptoms, may be prophylactic; and/or may be therapeutic based on partial or complete stabilization or cure of the disease and/or side effects due to the disease.
• treatment covers any treatment for a patient's condition, including:
• the compounds of the present invention can be prepared according to conventional organic chemical synthesis methods.
• the general preparation method of the compound of the general formula (I) of the present invention is as follows:
• the 5'-position acylated furanoarabinyl saponin I derivative (I; is hydrogen) can be isolated from the natural extract of the heavy saponin I and the corresponding organic acid R 2 C0 2 H, organic acid chloride R 2 COCl or organic
• the acid anhydride (R 2 CO) 20 is condensed and esterified; or the organic acid R 2 C0 2 H is activated to form an intermediate, and then reacted with the heavy saponin I to form a 5,-position acylated furan arabinose heavy saponin I derivative (I; is hydrogen); can also activate the hydroxyl group of the furan arabinosyl group of saponin I to form an intermediate, and then react with the organic acid R 2 C0 2 H to form 5,-position acylated furan arabinose A saponin I derivative (I; is hydrogen).
• R 2 in the formula (I) is the same as defined above in the formula (I).
• the above reaction is generally carried out in the presence of an alkali or an alkaline reagent.
• the base here may be, but is not limited to, an organic base.
• Solvents used include, but are not limited to, aprotic polar solvents such as dichloromethane (DCM), dimethyl sulfoxide (DMSO), dimethylformamide (DMF) or tetrahydrofuran (THF).
• DCM dichloromethane
• DMSO dimethyl sulfoxide
• DMF dimethylformamide
• THF tetrahydrofuran
• the reaction temperature of the above reaction is usually from 0 ° C to 50 ° C. It generally varies depending on the starting materials used and the base used.
• the starting material for the preparation reaction is saponin I.
• the raw material is obtained by extracting and separating natural products, and is also commercially available. All of the organic acids, organic anhydrides or organic acid chlorides from which the reaction is prepared can be purchased commercially.
• Protecting groups are those groups which, once attached to an active moiety (e.g., a hydroxyl group or an amino group), prevent these moieties from being interfered by subsequent reactions and which can be removed by conventional methods after the reaction.
• hydroxy protecting groups include, but are not limited to, alkyl, benzyl, decyl, trityl (ie, triphenylmethyl), acyl (eg, benzoyl, acetyl or HOOC-X).
• X is an alkylene, a subchain fluorenyl, cycloalkylene or arylene group, a silyl group (for example, trimethylsilyl, triethylsilyl and tert-butyl) Methylsilyl), alkoxycarbonyl, aminocarbonyl (eg, dimethylaminocarbonyl, methylethylaminocarbonyl, and phenylaminocarbonyl), alkoxymethyl, benzyloxymethyl, and alkyl armor base.
• amino protecting group examples include, but are not limited to, an alkoxycarbonyl group, an alkanoyl group, an aryloxycarbonyl group, an aryl-substituted alkyl group, and the like. Hydroxy and amino protecting groups have been discussed in T. W. Greene and P. G.. M. Wuts, Protective Groups in Organic Synthesis, 2nd Edition, John Wiley and Sons (1991). Both the base and the amino protecting group can be removed by a conventional method after the reaction.
• the invention also provides a pharmaceutical composition comprising Formula I of the invention.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising at least one compound of the formula I of the present invention as described above, and optionally a pharmaceutically acceptable excipient.
• Methods of preparing the pharmaceutical compositions include incorporation of suitable pharmaceutical excipients, carriers, diluents and the like.
• the pharmaceutical preparation of the present invention is produced by a known method, including a conventional mixing, dissolving or lyophilizing method.
• the compounds of the present invention can be formulated into pharmaceutical compositions and administered to a patient in a variety of routes suitable for the chosen mode of administration, e.g., orally or parenterally (by intravenous, intramuscular, topical or subcutaneous routes).
• the compounds of the invention may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable carrier such as an inert diluent or an edible carrier. They can be enclosed in hard or soft gelatin capsules and can be compressed into tablets.
• a pharmaceutically acceptable carrier such as an inert diluent or an edible carrier.
• the active compound may be combined with one or more excipients and in the form of swallowable tablets, buccal tablets, tablets, capsules, elixirs, suspensions, syrups, wafers, and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the ratio of such compositions and formulations may of course vary and may range from about 1% to about 99% by weight of a given unit dosage form.
• the amount of active compound is such that an effective dosage level can be obtained.
• Tablets, lozenges, pills, capsules, and the like may also contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium hydroperoxide; a disintegrating agent such as corn Starch, potato starch, alginic acid, etc.; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose or aspartame; or flavorings such as mint, wintergreen or cherry.
• a binder such as tragacanth, acacia, corn starch or gelatin
• an excipient such as dicalcium hydroperoxide
• a disintegrating agent such as corn Starch, potato starch, alginic acid, etc.
• lubricants such as magnesium stearate
• sweeteners such as sucrose, fructose, lactose or aspartame
• flavorings such as mint, wintergreen or cherry.
• any material used to prepare any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
• the active compound can be incorporated into a sustained release preparation and a sustained release device.
• the active compound can also be administered intravenously or intraperitoneally by infusion or injection.
• An aqueous solution of the active compound or a salt thereof, optionally a miscible non-toxic surfactant, can be prepared.
• the pharmaceutical dosage form suitable for injection or infusion may comprise a sterile aqueous solution or dispersion of the active ingredient (optionally encapsulated in a liposome) comprising a ready-to-use preparation suitable for sterile injectable or infusible solutions or dispersions. Or sterile powder.
• the final dosage form must be sterile, liquid, and stable under the conditions of manufacture and storage.
• the liquid carrier can be a solvent or liquid dispersion medium including, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and suitable mixtures thereof.
• Appropriate fluidity can be maintained, for example, by liposome formation, by maintaining the desired particle size in the case of dispersing agents, or by the use of surfactants.
• Microbial action can be prevented by various antibacterial and antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.).
• isotonic agents such as sugars, buffers or sodium chloride.
• Prolonged absorption of the injectable compositions can be brought about by the use of compositions which delay the absorbent (e.g., aluminum monostearate and gelatin).
• Sterile injectable solutions are prepared by combining the required active compound in a suitable solvent with the various other ingredients listed above, followed by filter sterilization.
• the preferred preparation methods are vacuum drying and lyophilization techniques which result in a powder of the active ingredient plus any additional ingredients present in the previously sterile filtration solution. .
• Useful solid carriers include comminuted solids (e.g., talc, clay, microcrystalline cellulose, silica, alumina, etc.).
• Useful liquid carriers include water, ethanol or ethylene glycol or a water-ethanol/ethylene glycol mixture, and the compounds of the present invention may be dissolved or dispersed in an effective amount, optionally with the aid of a non-toxic surfactant.
• Adjuvants e.g., flavors
• additional antimicrobial agents can be added to optimize the properties for a given use.
• Thickeners can also be used with liquid carriers to form coatable pastes, gels, ointments. , soap, etc., used directly on the user's skin.
• the therapeutic requirements of a compound or an active salt or derivative thereof depend not only on the particular salt selected, but also on the mode of administration, the nature of the disease to be treated, and the age and condition of the patient, ultimately depending on the attending physician or clinician decision.
• unit dosage form is a unit dosage unit containing a physical dispersion unit suitable for administration to humans and other mammalian bodies.
• the unit dosage form can be a capsule or tablet, or a lot of capsules or tablets.
• the amount of the unit dose of the active ingredient may vary or be adjusted from about 0.1 to about 1000 mg or more, depending on the particular treatment involved.
• the invention further provides the use of a compound of the invention or a composition comprising the compound for the preparation of a medicament, in particular an antitumor medicament. Accordingly, the invention provides a method of treating a tumor patient comprising administering to a patient in need of treatment a therapeutically effective amount of at least one compound of the invention.
• the 5'-acylated acyl arabinosyl saponin I derivative of the present invention or a pharmaceutically acceptable salt thereof can be used for the treatment of various tumors.
• leukemia multiple myeloma, lymphoma, liver cancer, gastric cancer, breast cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, colorectal cancer, osteosarcoma, melanoma, prostate cancer, human cervical cancer, glioma, nasal Tumors such as pharyngeal cancer, laryngeal cancer, esophageal cancer, and middle ear tumors.
• DMAP 4-dimethylaminopyridine
• DIC 7V, 7V'-diisopropylcarbodiimide
• saponin I 250 mg, 0.2924 mmol
• 2-furancarboxylic acid 36 mg, 0.2924 mmol
• 4-dimethylaminopyridine 7 mg, 0.0585 mmol
• 7V, 7V'-diisopropylcarbodiimide 36.3 mg, 0.23 mmol
• reaction mixture was concentrated and purified by silica gel chromatography elution elution elution elution elution elution elution elution elution elution elution elution elution -PP-10 (32.2 mg, yield: 11%).
• BS-PP-03 LC-MS (ELSD): Retention time: 1.56 min (98.61%), m/z 989.15.
• the same alkaline reagent and solvent are used to react the saponin I with isonicotinic acid
• BS-PP-04 LC-MS (ELSD): Retention time: 1.30 min (97.7%), m/z 961.5 (M+H) 481.0 (1/2M+H).
• the same basic reagent and solvent were used to react saponin I with p-fluorobenzoic acid to prepare compound BS-PP-06. :
• BS-PP-06 LC-MS (ELSD): Retention time: 1.56 min (91.34%), m/z 977.3.
• BS-PP-07 LC-MS (ELSD): Retention time: 1.37 min (99.21%), m/z 1003.4 (M+H), 502.0 (1/2M+H).
• BS-PP-08 LC-MS (ELSD): Retention time: 1.57 min (98.87%), m/z 1018.3 (M+Na).
• BS-PP-09 LC-MS (ELSD): Retention time: 1.53 min (99.01%), m/z 965.1.
• BS-PP-11 LC-MS (ELSD): Retention time: 1.39 min (97.77%), m/z 897.3.
• BS-PP-12 LC-MS (ELSD): Retention time: 1.45 min (99.44%), m/z 946.4 (M+Na).
• Leukemia cell line leukemia cell line: K562/adr (resistant chronic myeloid leukemia,
• CML CML
• NB4 acute promyelocytic leukemia, AML
• Kasumi-1 acute myeloid leukemia M2, AML-M2
• saponin I (PP I ) standard was purchased from Chengdu Mansite Biotechnology Co., Ltd., the saponin I derivative of the present invention
• 6000 well-grown leukemia cells were inoculated into the wells of a 96-well cell culture plate.
• the culture broth was a 1640 cell culture medium containing 10% fetal bovine serum.
• Add different concentrations of 5,-position acyl The furan arabinose-based heavy saponin I derivative was mixed and placed in a carbon dioxide (5% C0 2 ) cell incubator at 37 ° C for 72 hours.
• the viable cell concentration was then determined by the MTT method.
• the cell viability was set to 100% in the control group (without compound treatment), and cell viability (%) and 72-hour leukemia cell growth inhibition concentration (72-hour IC 5Q value and IC 9Q value) were calculated. .
• Table 1 shows that the 5,-position acylated furanoarabinyl saponin I derivative of the present invention can induce cell death of human chronic myeloid leukemia, acute myeloid leukemia and acute lymphocytic leukemia and inhibit the growth of these leukemia cells, Compared with the saponin I itself, the 5,-position acylated furanoarabinyl saponin I derivative of the present invention has markedly enhanced anti-leukemia cell activity, wherein the saponin I derivative BS-PP-04 of the present invention, BS-PP-08, BS-PP-10, BS-PP-1 K BS-PP-12 activity is particularly obvious, and the activity of anti-K562/adr (resistant chronic myeloid leukemia, CML) is increased by nearly 2 times or more; , BS-PP-04, BS-PP-06, BS-PP-08, BS-PP-10, BS-PP-11 anti-NB4 (acute promyelocytic leukemia, AML
• Table 1 Determination of growth inhibition concentration of leukemic cells, human multiple myeloma and lymphoma cells by 5,-position acylated furanoarabinosyl saponin I derivatives (72 hours, IC 5 (g/mL) value And IC 90 (g/mL) values).
• Human solid tumor cell lines A549 (human lung cancer), SK-OV-3 (ovarian cancer cells), all purchased from the China Center for Type Culture Collection; RKO (human colon adenocarcinoma), MG-63 (osteosarcoma), All purchased from Shanghai Fuxiang Biotechnology Co., Ltd.; Hela (human cervical cancer cells), received from the Institute of Cancer Research, Zhejiang University.
• Table 2 shows that the 5,-position acylated furanoarabinyl saponin I derivative of the present invention can induce human solid tumor cell death and inhibit the growth of these tumor cells, compared with the saponin I itself, 5 of the present invention,
• the at-position acylated furanoarabinyl saponin I derivative is significantly enhanced against solid tumor cell activity, wherein the heavy saponin I derivative of the present invention BS-PP-04, BS-PP-08, BS-PP-10 BS-PP-1 BS-PP-12 is particularly active, and the activity against A549 (human lung cancer) is nearly doubled or more.
• Table 2 Determination of the half-growth inhibition concentration of the 5,-position acylated furanoarabinyl saponin I derivative on human myeloma cells and solid tumor cells (72 hours, IC 5 (g/mL) value and IC 90 (g/mL) value)

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• 2013
  • 2013-06-13 DK DK13805106.5T patent/DK2862869T3/en active
  • 2013-06-13 US US14/407,622 patent/US9353146B2/en not_active Expired - Fee Related
  • 2013-06-13 WO PCT/CN2013/077165 patent/WO2013185613A1/fr not_active Ceased
  • 2013-06-13 EP EP13805106.5A patent/EP2862869B1/fr not_active Not-in-force
  • 2013-06-13 JP JP2015516430A patent/JP2015523349A/ja active Pending

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